APPLICATION NUMBER€¦ · Jules O’Rear, PhD, Clinical Virology Team Leader Mario Sampson, PhD,...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761169Orig1s000

ADMINISTRATIVE and CORRESPONDENCE

DOCUMENTS

IND 125507MEETING MINUTES

Regeneron Pharmaceuticals, Inc. Attention: Janie Parrino, MD Senior Director, Regulatory Affairs 777 Old Saw Mill River Road Tarrytown, NY 10591-6707

Dear Dr. Parrino:

Please refer to your investigational new drug application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for REGN3470-3471-3479 (REGN-EB3).

We also refer to the telecon between representatives of your firm and the FDA on October 21, 2019. The purpose of the meeting was to discuss the content and format of a BLA.

A copy of the official minutes of the telecon is enclosed for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes.

If you have any questions, call me, at (301) 796-0824.

Sincerely,

{See appended electronic signature page}

Elizabeth Thompson, MS Senior Program Management Officer Division of Antiviral Products Office of Antimicrobial Products Center for Drug Evaluation and Research

Enclosure: Meeting Minutes

Reference ID: 4511561

MEMORANDUM OF MEETING MINUTES

Meeting Type: Meeting Category:

B Pre-BLA

Meeting Date and Time: Meeting Location:

October 21, 2019; 10:00 AM – 11:30 AM EST Teleconference

Application Number: Product Name:

IND 125507 REGN3470-3471-3479 (REGN-EB3)

Indication: Sponsor Name:

Treatment of Ebola virus infection Regeneron Pharmaceuticals, Inc.

FDA ATTENDEES

Office of New Drugs Katherine Schumann, MS, OND Policy Staff

Office of Antimicrobial Products Barbara Styrt, MD, Medical Officer

Division of Antiviral Products Debbie Birnkrant, MD, Director Jeff Murray, MD, MPH, Deputy Director Karen Winestock, Chief, Project Management Staff Elizabeth Thompson, MS, Senior Program Management Officer Ben Lorenz, MD, Clinical Reviewer Kim Struble, PharmD, Clinical Team Leader John Dubinion, PhD, Nonclinical Reviewer Chris Ellis, PhD, Nonclinical Team Leader Eric Donaldson, PhD, Clinical Virology Reviewer Jules O’Rear, PhD, Clinical Virology Team Leader Mario Sampson, PhD, Clinical Pharmacology Reviewer Su-Young Choi, PhD, Clinical Pharmacology Team Leader LaRee Tracy, PhD, Statistics Reviewer Thamban Valappil, PhD, Statistics Team Leader

Office of Scientific Investigations Karen Bleich, MD, Medical Officer

Office of Biotechnology Products (OBP)/Office of Product Quality (OPQ) Marquita Burnett, MPH, Regulatory Business Project Manager


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Tzanko Stantchev, PhD, Drug Product Reviewer Marjorie Shapiro, PhD, Lab Chief

Counter-Terrorism and Emergency Coordination Staff Gerald Poley, MD, Medical Officer Susan McDermott, MD, Medical Officer Kara Bertolaccini, PharmD, Regulatory Project Manager

SPONSOR ATTENDEES

Regeneron

Ned Braunstein, MD, Sr VP, Regulatory Affairs Janie Parrino, MD, Sr Director, Regulatory Affairs Elizabeth Bradley, MS, PharmD, Manager, Regulatory Affairs Leah Lipsich, PhD, VP, Strategic Program Direction Yasmin Khan, MS, MPH, Director, Development Program Management Eduardo Forleo Neto, MD, MSc, Exec Director, Clinical Sciences Sumathi Sivapalasingam, MD, Sr Director, Clinical Sciences Bret Musser, PhD, Sr Director, Biostatistics Meilin Huang, PhD, Principal Biostatistician Christos Kyratsous, PhD, VP, Research Alina Baum, PhD, Staff Scientist, Therapeutic Focus Area Joel Kantrowitz, PhD, Sr Director, Preclinical PK/PD Michael Partridge, PhD, Associate Director, Bioanalytical Sciences Susan Irvin, PhD, PMP, Scientist, Bioanalytical Sciences Kenneth Turner, PhD, Director, Clinical Pharmacology Romana Hosain, MD, MPH, Sr. Director, Risk Management Simon Eng, MD, Director, Risk Management

BARDA David Boucher, PhD, Chief, Antivirals & Antitoxins, CBRN Danielle Turley, PhD, Project Officer, AVAT, CBRN Michael Merchlinsky, PhD, Scientific Program Manager, CBRN Paul Roney, PhD, DABT, Regulatory Specialist, RQA James Wangelin, MS, MBA, RAC, Regulatory Specialist, RQA

1.0 BACKGROUND

Regeneron Pharmaceuticals, Inc. (Regeneron) requested a Type B pre-BLA meeting on September 20, 2019 to discuss the content and format of a BLA application for REGN3470-3471-3479, also known as REGN-EB3. Having recently received Breakthrough Therapy Designation, this meeting also serves as the Breakthrough Therapy-Initial Comprehensive meeting. The background package was submitted with

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov


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the meeting request, and an addendum that included non-human primate (NHP) data and a supplemental statistical analysis plan (SAP) to the NIH PALM RCT SAP was provided on October 9, 2019.

REGN-EB3, is a cocktail of three human IgG1 monoclonal antibodies (mAbs) directed against different, non-overlapping epitopes on Ebola virus (EBOV) glycoprotein (GP).

Regeneron initiated the REGN-EB3 development program under the Animal Rule, but with the advent of the Ebola outbreak in the North Kivu province of the Democratic Republic of the Congo (DRC) in 2018, Regeneron has accrued data in Ebola-infected patients and will follow a traditional pathway to approval. Regeneron proposes the randomized controlled trial (RCT; PALM study, protocol 19-I-0003) conducted by the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH, IND 125530) as the primary basis of efficacy and safety for the BLA with the expanded access program (EAP, R3470-3471-3479- EBOV-1846) and the first-in-human study (FIH, R3470-3471-3479-HV-1528) in normal healthy volunteers providing supportive information. Additionally, Regeneron will provide pharmacokinetic (PK) data in uninfected and infected NHPs, efficacy data in infected NHPs, and supportive data in guinea pigs.

REGN-EB3 was granted orphan-drug designation for the treatment of Ebola virus infection on July 14, 2016 and granted Breakthrough Therapy Designation on September 3, 2019.

FDA granted the meeting on September 27, 2019 and sent Preliminary Comments to Regeneron on October 15, 2019.

2.0 DISCUSSION

2.1. Clinical

Question 1: Does the Agency agree that a single IV infusion of 150 mg/kg of REGN-EB3 is the to-be-marketed dose provided the final results from the PALM study are consistent with the data shared to date?

FDA Response to Question 1: We agree. Although the 150 mg single dose is acceptable for an initial marketing approval, we do not have enough data to determine whether this is the optimal dose. We recommend that you propose a plan to conduct additional nonclinical and/or clinical studies post-approval to further optimize the dosing regimen.

We have recommended assessment of higher doses, particularly for subjects who present with CT values

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Sponsor’s Response: The Sponsor thanks the Agency for the response. The Sponsor believes that the best way to address this question is through clinical data and will submit a proposal during the review of the BLA. If the Agency agrees with the suggested timing for a proposal, no further discussion is needed at the TC.

Discussion: No further discussion occurred.

Question 2: The safety database will consist of data from patients with Ebola virus disease in the PALM randomized controlled study and the expanded access program. Given differences in the data collection, the Sponsor proposes not to integrate the safety data. Does the Agency agree with this proposal?

FDA Response to Question 2: We agree that integrating the safety data from the EAP presents several challenges due to inconsistencies with data collection; however, your safety database should include any subjects in the EAP for whom the investigator can be verified. We can only determine whether the quality is adequate when all available data are submitted.

While much of the data from the EAP may not be appropriate for the Integrated Summary of Safety in Module 5, a descriptive summary of other supportive safety experience from the EAP may be suitable for Module 2.7.4, Summary of Clinical Safety. Please also see our response to Question 4; however, you may want to consider a submission structured like Example 4 in the Guidance for Industry Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document (https://www.fda.gov/media/75783/download).

Sponsor’s Response: The Sponsor appreciates that the Agency agrees that the EAP and RCT data will not be integrated. However, at the TC, the Sponsor requests clarification on the EAP data to be included and the format. In particular, the Sponsor would like to understand what the Agency means by “for whom the investigator can be verified.” The Sponsor is currently aware of 231 REGN-EB3 treated patients in the EAP and is anticipating providing all data from the WHO/INRB tracker as well as data provided by word documents from MSF. To facilitate the discussion, please see the separate slide deck which provides further details on the EAP data sources.

Discussion: Regeneron presented slide number 4. FDA clarified that Regeneron should provide everything they have to include any descriptive data that would add to the safety database, and that Regeneron should attempt to provide disclosure forms for all investigators or show due diligence. Regeneron noted they have 1572’s for the main investigators, but they do not have names/credentials of those in the field. Regeneron stated they would provide data as accurately represented in field with credentialed investigators or provide evidence of due diligence.



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Question 3: Does the Agency agree with the Sponsor’s proposal regarding patient narratives for the PALM RCT and EAP data?

FDA Response to Question 3: We agree. If any are available, however, narratives from the EAP of non-fatal SAEs that the investigator determined to be related to the study drug should also be submitted. Whether clinical and laboratory findings in patients with EVD confound safety assessments, however, should not be concluded a priori.

Sponsor’s Response: The Sponsor appreciates the Agency’s response and would like to provide 2 points of clarification:

As noted in the pre-BLA briefing book, unlike in the RCT, the Sponsor provided case report forms were not completed for the EAP. Given that all patients were hospitalized prior to treatment and the nature of the patients’ underlying disease, fatal outcome was the only seriousness criterion that could be reasonably applied to the data provided to the Sponsor to define an SAE. Therefore, there will not be any non-fatal SAEs provided for the EAP.

For the RCT, the Sponsor is proposing writing narratives only for the REGN-EB3 treatment arm.

If the Agency agrees with the above, no further discussion is required at the TC.


Question 4: a) The Sponsor proposes that given the size of the clinical development program, the information that would typically be included in all the 2.7 Modules could be sufficiently summarized within the page limitations and scope of the 2.5 Clinical Overview document, with accompanying details in the clinical study reports (Module 5). Does the Agency agree with this proposal?

b) Assuming the Agency agrees with providing only the 2.5 Clinical Overview, does the Agency agree with the proposed content and format of the Clinical Overview?

FDA Response to Question 4: Ideally, the 2.5 Clinical Overview document should contain a more concise text summary that includes only important tables and figures. However, you might want to consider structuring your submission as suggested by Guidance in our response to Question 2.

Sponsor’s Response: The Sponsor thanks the Agency for the response and requests additional clarification as noted in the response to Question 2. The proposal in the pre-BLA briefing book by the Sponsor for the Module 2.5 content was believed to meet the requirements regarding presentation of concise text summary and inclusion of important



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tables and figures. Further details for both the RCT and EAP will be provided in the respective CSRs. To facilitate the discussion please see the separate slide deck.

Discussion: Regeneron presented slide number 5. FDA stated they agree with the Sponsor’s proposal and noted that the information that will support the regulatory decision of the application may be included in Module 2.5 provided the clinical overviews are concise and brief. The reviewer may be referred to the Integrated Summaries (Module 5.3.5.3, a mandatory module) for any supplementary information (e.g., additional tables or figures). If the Sponsor believes that the information intended to be submitted under Module 2.7 (a mandatory module) is covered appropriately by the content in 2.5, a document in 2.7 that refers the reviewer to Module 2.5 must be provided.

Question 5: When the Sponsor was pursuing the Animal Rule pathway, the Agency requested that the Sponsor assess safety and immunogenicity in healthy volunteers following administration of a second dose after an appropriate washout period. Since the intended use of the product is through administration of a single dose, is this additional study still required? If the Agency still requires this study, we propose this be evaluated as a post-marketing commitment. Does the Agency agree?

FDA Response to Question 5: We agree that the assessment of safety and immunogenicity in healthy volunteers following a second dose may be evaluated as a post-marketing requirement.

Sponsor’s Response: The Sponsor thanks the Agency for the response. No further discussion is required at the TC.


Question 6: Does the Agency agree that a REMS is not needed?

FDA Response to Question 6: Based on the data currently available, we do not foresee a need for a REMS.



2.2. Statistical

Question 7: Does the Agency agree with the datasets described below to be included in the BLA with the individual clinical study reports (CSRs)?



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FDA Response to Question 7: It is our understanding that you are working with NIAID to determine the exact content and structure of data they will provide from the PALM trial. Ideally, we prefer to receive the entire content of the PALM trial, i.e. data from all randomized treatment arms, not only those data from the ZMapp and REGN-EB3 arms as our review will be based on the complete trial as designed. We have communicated this need to NIAID as well. Therefore, we ask that you work with NIAID to ensure that your submission include the complete PALM trial data in CDISC format.

The proposed data structures for the EAP and FIH data are acceptable.

Sponsor’s Response: The Sponsor requests further discussion at the TC. The Sponsor has concerns with the Agency’s request to include data from other company’s molecules (beyond the protocol defined comparator arm) in our CSRs and BLA modules.

Discussion: The FDA asked how will they verify that patients in two treatments arms received treatment as per the randomization schedule and identify any deviations? Regeneron noted they would obtain the original randomization schedule from NIH and will compare it against the randomization in the two treatment arms (ZMapp and REGN-EB3). FDA agreed.

Question 8: Does the Agency agree that the Statistical Analysis Plan for the PALM RCT (Protocol 19-I-0003) as proposed by NIAID is sufficient to support registration of REGN-EB3?

FDA Response to Question 8: We agree that the primary efficacy analysis of day 28 all-cause mortality should be as specified in the NIH/NIAID SAP, without deviations.

Please clarify how any missing day 28 assessments (missing not due to death) will be treated in the primary efficacy analysis in the MITT set. This is not clearly stated in sections 5.5.1 or

In addition, we received your draft SAP addendum and have the following preliminary comments to be addressed in an updated/final SAP. Consistent with the NIAID SAP, the primary efficacy analysis should be performed in all randomized patients. As such, the MITT set, including all randomized patients except those randomized during the period in which ZMapp was unavailable for randomization, should serve as the primary efficacy analysis set. We do not agree (b) (4)

5.5.2 of the draft SAP.

Sponsor’s Response: The Sponsor requests further discussion at the TC regarding the primary and sensitivity analysis populations to clarify the following points:

The NEJM publication excludes a patient who was confirmed not to be PCR positive. Per the NIAID/NIH SAP, this person should be included in analyses. The Sponsor proposes the NIAID/NIH SAP population for the primary efficacy analyses.



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The Sponsor requests clarification on the definition and role of the MITT population. This population is different than the NIH/NIAID SAP primary analysis population. The Sponsor proposes the MITT population as a sensitivity analysis.

o The Sponsor notes that the MITT population identified by the Agency does not match the Sponsor proposal in the supplemental SAP. The Sponsor proposes to include the 7 patients who were randomized when ZMapp was not available.

To facilitate the discussion, the Sponsor has provided a separate slide that outlines the various patient populations and the proposals above.

With regard to the handling of missing data, it is our understanding that there is an outcome for each patient, either death or follow-up at Day 28. If there are missing outcomes, the Sponsor will impute the missing Day 28 assessment as an outcome of death.

Discussion: Regeneron presented slide number 3. FDA clarified that the preliminary responses were based on the REGN SAP, which describes a population that differs from that stated in the NIH SAP. FDA also noted that they consider the NIH SAP the basis for the primary analysis and not the NEJM manuscript. The NIH SAP indicates that the primary efficacy population is the intent-to-treat. Regeneron clarified that their primary efficacy population will be the ITT concurrent population, which includes all randomized patients after REGN-EB3 was added to the trial (but excluding patients randomized when ZMapp was unavailable), and it will include the 12 subjects who died prior to infusion and the one patient who was randomized but had a false positive PCR. A sensitivity analysis, using all randomized patients including those not concurrent, would be performed along with an analysis in the MITT, which includes all patients including those randomized prior to the introduction of REGN-EB3 to the trial and patients randomized during the time ZMapp was unavailable. FDA agreed with this approach. FDA further noted that any discordant findings across the populations will need to be described and explained in the BLA. Regeneron agreed to update the SAP addendum reflecting these agreed upon populations.

2.3. Regulatory

Question 9: The Sponsor (b) (4)

FDA Response to Question 9: We do not agree. Your safety update report should include any additional descriptive safety data from the extension phase of the PALM trial. Please work with NIH regarding how this data can be shared (e.g., identification of a timepoint for an interim analysis). Additional data within 2 months after submission of the BLA would be acceptable. As discussed in Question 2, we do not expect data from



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the EAP to be fully verified and integrated into the safety database; however, it would be acceptable for your safety update to include descriptive reports.

Sponsor’s Response: The Sponsor requests further discussion at the TC. (b) (4)

Discussion: Regeneron presented slide number 6. Regeneron noted they planned for a December cutoff date and could provide a safety update to the Division in February (noting the 2-month request from the Agency). FDA agreed with the content of the safety update.

Question 10: Does the Agency agree with the Sponsor’s proposed dossier content, structure, format and eTOC?

FDA Response to Question 10: Please see our responses to Questions 2 and 4.

Sponsor’s Response: The Sponsor thanks the Agency for the response and requests additional clarification as noted in the response to Questions 2 and 4.

Discussion: Please see the discussion under Question 4.

Question 11: Does the Agency agree that there are no studies to be considered “covered clinical studies” for the purposes of Regeneron providing financial disclosure and summary level clinical site data for BIMO requirements?

FDA Response to Question 11: We agree that the phase 1 and the EAP studies are not considered “covered clinical studies”; however, the PALM trial is considered a “covered clinical study”. While we acknowledge that the study was conducted by NIAID, you are relying on the data from the PALM study to support the effectiveness of REGN-EB3 per 21 CFR 54.3; therefore, you must comply with the financial disclosure requirements under, 21 CFR 54.4. You should discuss with NIAID the information NIAID collected with respect to financial disclosure and summary level clinical site data for the BIMO requirements. If NIAID does not have these data, or only has partial documentation, the BLA should contain a rationale to document due diligence to comply with the requirements.



Question 12: (b) (4)



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(b) (4)

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(b) (4)

FDA Response to Question 12: We do not agree.

(b) (4)



Question 13: Does the Agency agree that if deemed eligible for priority review andapproval, the application for REGN-EB3 for treatment (b) (4) of Ebola virus infection is eligible for a tropical disease priority review voucher?

FDA Response to Question 13: We have reviewed your rationale for why you anticipate eligibility for a tropical disease PRV. At this time, the Division’s best assessment is that your proposed application for REGN-EB3 for the treatment of Ebola virus infection will meet the requirement that the application is intended to prevent or treat a tropical disease described in section 524(a)(3).

However, as you described in your meeting package, section 524(a)(4)(iii) of the FD&C Act requires that the application contain reports of one or more new clinical investigations (other than bioavailability studies) that are essential to the approval of the application and conducted or sponsored by the sponsor. Currently, the Agency evaluates whether this requirement is met on a case-by-case basis when the NDA or BLA is under review. In your request for a tropical disease priority review voucher, please provide detailed information on the support you provided for the PALM study and your rationale for why the phase 1 study should be considered a “new clinical investigation.”



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We note there is no similar requirement for new clinical investigations for the material threat MCM PRV program. If you plan to request a PRV for a product intended to treat or prevent a disease/material threat that is on both the tropical disease and material threat lists for purposes of PRV eligibility, you may wish to consider which voucher program is a better fit for your specific product and development program.

Although review classification (priority or standard) is not determined until an application is received, we anticipate, with the exception of any unforeseen circumstances, that priority review for the REGN-EB3 BLA will be granted. For additional information, see the FDA Guidance for Industry: “Expedited Programs for Serious Conditions-Drugs and Biologics.”

Sponsor’s Response: The Sponsor requests further discussion at the TC. The Sponsor believes that REGN-EB3 should be eligible for the tropical disease PRV for the reasons previously provided in the pre-BLA briefing book. The tropical disease PRV is preferred by the Sponsor as this voucher can be applied to both initial and supplemental BLAs whereas the MCM PRV can only be applied to initial BLAs. So as not to miss an opportunity for a PRV for this program, the Sponsor proposes submitting requests for both the tropical disease and MCM PRV with the understanding that only one will be granted.

Discussion: Regeneron presented slide number 7. FDA agreed with Regeneron’s proposal to submit requests for both the tropical disease and medical countermeasure PRVs.

ADDITIONAL RECOMMENDATIONS

Clinical Virology

1.No resistance data or description of the epitopes for the REGN-EB3 cocktail have been provided to date. These data are useful in assessing the durability of the cocktail in future outbreaks. Clinical Virology strongly recommends that characterization of the epitopes be completed and submitted with the BLA, however, if this is not possible, we request that the sponsor provide all data generated to date in the BLA along with available resistance data. Please provide the timeline when these study reports will be submitted to the BLA.

Sponsor’s Response: To date we have mapped the epitopes of REGN3470, REGN3471, and REGN3479 by negative stain EM (Pascal, K. E. et al. J Infect Dis 218, S612–S626 (2018)) and hydrogen-deuterium exchange (HDX). We assessed the amino acid conservation of the mapped epitopes using 2614 publicly available Zaire ebola virus GP sequences. The data will be summarized and provided in the initial BLA or during the FDA review cycle. Additionally, we are in the process of generating higher resolution epitope mapping data using cryo-EM to more precisely



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define the amino acid contacts of our antibodies. Upon availability, we will refine our conservation analysis. At present, our best estimate of report availability is 4Q2020.

We have also assessed whether we can detect REGN-EB3 treatment induced escape by analyzing viral RNA sequences from NHP Study 2015-002. No

(b) (4)

mutations associated with treatment were identified.

Discussion: FDA agreed with Regeneron’s proposal to submit the requested resistance data and description of the epitopes within 60 days of the original BLA application.

2.Please be aware that the division requests raw fastq files for all resistance assessments performed by next generation sequencing in clinical trials and animal studies used to support approval of antiviral drugs. We would encourage you to provide a mock data submission of fastq sequences and your analyses of those sequences prior to the official submission so that we can ensure that all of the necessary information is provided for full review of the larger dataset. Please refer to the Technical Specification, Submitting Next Generation Sequencing Data to the Division of Antiviral Products Experimental Design and Data Submission, which can be downloaded at: https://www.fda.gov/media/129126/download.

Sponsor’s Response: The Sponsor will provide a mock data submission this November.

3.The T544I polymorphism analysis is no longer necessary given the clinical data. However, we would be interested in reviewing any data you have generated to date on the T544I polymorphism.

Sponsor’s Response: The Sponsor will provide sequencing data from NHP Study 2015-002 as well as binding data of REGN3470, REGN3471, and (b) (4)

REGN3479 to virus like particles (VLPs) expressing Zaire ebolavirus GP with the T544I polymorphism during the BLA review cycle.

3.0 ADDITIONAL INFORMATION

DISCUSSION OF THE CONTENT OF A COMPLETE APPLICATION

The content of a complete application was discussed. The Division noted that major components of the application are expected to be submitted with the original application and are not subject to agreement for late submission. FDA agreed that the following minor application components may be submitted within 60 calendar days after the submission of the original application: Clinical Virology resistance data and description of the epitopes for the REGN-EB3 cocktail.




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Post-meeting Comment: Minor application components are to be submitted within 30 days after the submission of the original application. Given the importance of this product, the FDA has agreed to an altered timeline for the submission of the clinical virology resistance data.

In addition, the Division noted that a chemistry pre-submission meeting is scheduled for October 31, 2019. A summary of agreements reached at that meeting will be documented in the respective meeting minutes.

All applications are expected to include a comprehensive and readily located list of all clinical sites and manufacturing facilities included or referenced in the application.

No discussion was held on the need for a REMS, other risk management actions and, where applicable, the development of a Formal Communication Plan. The FDA referenced the preliminary comments which concluded that based on the currently available data, a REMS is not required at this time.

PREA REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Because this drug product for this indication has an orphan drug designation, you are exempt from these requirements. Please include a statement that confirms this finding, along with a reference to this communication, as part of the pediatric section (1.9 for eCTD submissions) of your application. If there are any changes to your development plans that would cause your application to trigger PREA, your exempt status would change.

PRESCRIBING INFORMATION

In your application, you must submit proposed prescribing information (PI) that conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57 including the Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30, 2015). As you develop your proposed PI, we encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information1 and Pregnancy and Lactation Labeling Final Rule2 websites, which include:

1 https://www.fda.gov/drugs/laws-acts-and-rules/plr-requirements-prescribing-information 2 https://www.fda.gov/drugs/labeling/pregnancy-and-lactation-labeling-drugs-final-rule U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov


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The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products.

The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information related to pregnancy, lactation, and females and males of reproductive potential.

Regulations and related guidance documents.

A sample tool illustrating the format for Highlights and Contents, and

checklist of important format items from labeling regulations and guidances.

FDA’s established pharmacologic class (EPC) text phrases for inclusion in the Highlights Indications and Usage heading.

Pursuant to the PLLR, you should include the following information with your application to support the changes in the Pregnancy, Lactation, and Females and Males of Reproductive Potential subsections of labeling. The application should include a review and summary of the available published literature regarding the drug’s use in pregnant and lactating women and the effects of the drug on male and female fertility (include search parameters and a copy of each reference publication), a cumulative review and summary of relevant cases reported in your pharmacovigilance database (from the time of product development to present), a summary of drug utilization rates amongst females of reproductive potential (e.g., aged 15 to 44 years) calculated cumulatively since initial approval, and an interim report of an ongoing pregnancy registry or a final report on a closed pregnancy registry. If you believe the information is not applicable, provide justification. Otherwise, this information should be located in Module 1. Refer to the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products – Content and Format.

Prior to submission of your proposed PI, use the SRPI checklist to ensure conformance with the format items in regulations and guidances.

MANUFACTURING FACILITIES

To facilitate our inspectional process, we request that you clearly identify in a single location, either on the Form FDA 356h, or an attachment to the form, all manufacturing facilities associated with your application. Include the full corporate name of the facility and address where the manufacturing function is performed, with the FEI number, and specific manufacturing responsibilities for each facility.



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Also provide the name and title of an onsite contact person, including their phone number, fax number, and email address. Provide a brief description of the manufacturing operation conducted at each facility, including the type of testing and DMF number (if applicable). Each facility should be ready for GMP inspection at the time of submission.

Consider using a table similar to the one below as an attachment to Form FDA 356h. Indicate under Establishment Information on page 1 of Form FDA 356h that the information is provided in the attachment titled, “Product name, NDA/BLA 012345, Establishment Information for Form 356h.”

Site Name

(1)

Site Address

Federal Establishment Indicator (FEI) or Registration Number (CFN)

Drug Master File Number (if

applicable )

Manufacturing Step(s)

or Type of Testing [Establishment function]

(2)

Corresponding names and titles of onsite contact:

Site Name

(1)

Site Address

Onsite Contact (Person, Title)

Phone and Fax number

Email address

(2)

OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS

The Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA investigators who conduct those inspections. This information is requested for all major trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested items are provided elsewhere in submission in the format described, the Applicant can describe location or provide a link to the requested



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information.

Please refer to the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications.3

NONPROPRIETARY NAME

On January 13, 2017, FDA issued a final guidance for industry Nonproprietary Naming of Biological Products, stating that, for certain biological products, the Agency intends to designate a proper name that includes a four-letter distinguishing suffix that is devoid of meaning.

Please note that certain provisions of this guidance describe a collection of information and are under review by the Office of Management and Budget under the Paperwork Reduction Act of 1995 (PRA). These provisions of the guidance describe the submission of proposed suffixes to the FDA, and a sponsor’s related analysis of proposed suffixes, which are considered a “collection of information” under the PRA. FDA is not currently implementing provisions of the guidance that describe this collection of information.

However, provisions of the final guidance that do not describe the collection of information should be considered final and represent FDA’s current thinking on the nonproprietary naming of biological products. These include, generally, the description of the naming convention (including its format for originator, related, and biosimilar biological products) and the considerations that support the convention.

Your proposed 351(a) BLA would be within the scope of this guidance. As such, FDA intends to assign a four-letter suffix for inclusion in the proper name designated in the license at such time as FDA approves the BLA.

4.0 ISSUES REQUIRING FURTHER DISCUSSION

There were no issues requiring further discussion.

5.0 ACTION ITEMS

Action Item/Description Owner Due Date Amended SAP Sponsor Asap

3 https://www.fda.gov/media/85061/download U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov



IND 125507Page 17

6.0 ATTACHMENTS AND HANDOUTS

Copy of presented slides from Regeneron

U.S. Food and Drug Administration Silver Spring, MD 20993www.fda.gov


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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

/s/

ELIZABETH G THOMPSON 10/25/2019 03:40:26 PM


CDER Breakthrough Therapy Designation Determination Review Template (BTDDRT)

IND/NDA/BLA # 125507

Request Receipt Date 16 August 2019

Product REGN-EB3

Indication Treatment of patients with Ebola virus infection

Drug Class/Mechanism of Action

Cocktail of three recombinant human IgG1 mAbs directed against Ebola virus (EBOV) glycoprotein (GP)

Sponsor Regeneron Pharmaceuticals Inc.

ODE/Division OAP/DAVP

Breakthrough Therapy Request (BTDR) Goal Date (within 60 days of receipt)

15 October 2019

Note: This document must be uploaded into CDER’s electronic document archival system as a clinical review: REV-CLINICAL-24 (Breakthough Therapy Designation Determination) even if the review is attached to the MPC meeting minutes and will serve as the official primary Clinical Review for the Breakthrough Therapy Designation Request (BTDR). Link this review to the incoming BTDR. Note: Signatory Authority is the Division Director.

Section I: Provide the following information to determine if the BTDR can be denied without Medical Policy Council (MPC) review.

1. Briefly describe the indication for which the product is intended (Describe clearly and concisely since the wording will be used in the designation decision letter):

REGN-EB3 is being developed for the treatment of Ebola virus infection, which is a serious and life-threatening disease, characterized by acute hemorrhagic fever, with historical case fatality rates (CFR) ranging from 25 to 90%. The CFR in the 2014-2016 West African outbreak was 63% in confirmed cases with recorded outcomes. As of 6 August 2019 in the ongoing outbreak in the North Kivu and Ituri provinces of the Democratic Republic of the Congo (DRC), there have been 2687 confirmed cases with 1772 deaths among the confirmed cases for a CFR of 66%.

2. Are the data supporting the BTDR from trials/IND(s) which are on Clinical Hold? YES NO

3. Was the BTDR submitted to a PIND? YES NO If “Yes” do not review the BTDR. The sponsor must withdraw the BTDR. BTDR’s cannot be submitted to a PIND.

N/A

If 2 above is checked “Yes,” the BTDR can be denied without MPC review. Skip to number 5 for clearance and sign-off. If checked “No”, proceed with below:

4. Consideration of Breakthrough Therapy Criteria:

YES NO a. Is the condition serious/life-threatening1)?

1 For a definition of serious and life threatening see Guidance for Industry: “Expedited Programs for Serious Conditions––Drugs and Biologics” http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf 1

http://www

If 4a is checked “No,” the BTDR can be denied without MPC review. Skip to number 5 for clearance and sign-off. Ifchecked “Yes”, proceed with below:

b. Are the clinical data used to support preliminary clinical evidence that the drug may demonstrate substantialimprovement over existing therapies on 1 or more clinically significant endpoints adequate and sufficientlycomplete to permit a substantive review?

YES, the BTDR is adequate and sufficiently complete to permit a substantive review Undetermined NO, the BTDR is inadequate and not sufficiently complete to permit a substantive review; therefore, the request must be denied because (check one or more below):

i. Only animal/nonclinical data submitted as evidence ii. Insufficient clinical data provided to evaluate the BTDR

(e.g. only high-level summary of data provided, insufficient information about the protocol[s])

iii. Uncontrolled clinical trial not interpretable because endpoints are not well-defined and the natural history of the disease is not relentlessly progressive (e.g. multiple sclerosis, depression)

iv. Endpoint does not assess or is not plausibly related to a serious aspect of the disease (e.g., alopecia in cancer patients, erythema chronicum migrans in Lyme disease)

v. No or minimal clinically meaningful improvement as compared to available therapy2/ historical experience (e.g.,

__________________________________________________________________________________________________

Section II: If the BTDR cannot be denied without MPC review in accordance with numbers 1-3 above, or if the Division is recommending that the BTDR be granted, provide the following additional information needed by the MPC to evaluate the BTDR.

7. A brief description of the drug, the drug’s mechanism of action (if known), the drug’s relation to existing therapy(ies), and any relevant regulatory history. Consider the following in your response.

Ebola virus is transmitted by exposure to infected bodily fluids from an infected individual through abraded skin, mucosal tissues, or through parenteral exposure. The incubation period varies between 2 and 21 days with an average period of 6-12 days. Early symptoms of Ebola virus infection include fever, myalgias, chills, and general malaise, followed by onset of gastrointestinal symptoms such as diarrhea and abdominal pain. In one study, less than 50% of patients actually developed hemorrhagic symptoms such as petechiae, conjunctival hemorrhage, epistaxis, melena, hematemesis, and shock. Patients who progress to death often develop more severe symptoms 7 to 14 days after symptom onset, while those who recover have improvement of symptoms during the same time period. Rapid viral replication is one contributor to the development of severe disease: viremia in non-survivors can be 100- to 1000-fold higher than in survivors.

REGN-EB3 is a cocktail of three recombinant human IgG1 monoclonal antibodies (mAbs): REGN3470, REGN3471 and REGN3479, which are combined in a 1:1:1 ratio and each targets a different, non-overlapping Zaire ebolavirus (EBOV) glycoprotein (GP) epitope. The three mAbs were generated when Regeneron immunized their proprietary VelocImmune®

mice, which express human antibody genes, with DNA encoding the EBOV spike glycoprotein. Each mAb is manufactured in Chinese hamster ovary cell line

but each mAb has different Fc effector (killing infected cells that express the Ebola virus

(b) (4) (b) (4)

glycoprotein on the cell surface) and neutralizing (blocking virus entry into cells) characteristics. One of the mAbs (REGN3471) binds to secreted GP (sGP), which is present at much higher concentrations than EBOV particles in human sera. There are concerns that sGP may act as a decoy to absorb the REGN3471 mAb and limit its effective concentration. In the current outbreak in the DRC, REGN-EB3 is one of four investigational therapeutics provided as expanded access under the World Health Organization’s (WHO) ethical framework known as Monitored Emergency Use of Unregistered Interventions (MEURI).

Among the currently available investigational therapeutics, only ZMappTM (a triple mAb cocktail, by Mapp Biopharmaceutical, Inc.) has been previously assessed in a randomized controlled clinical trial. In 2015 during the West African outbreak of EBOV, a randomized controlled trial of ZMapp plus current standard of care (cSOC) compared with cSOC alone in patients with Ebola virus disease (EVD) diagnosed by RT-PCR was conducted. ZMapp was administered at a dose of 50 mg/kg given every three days for a total of three doses. Minimum cSOC requirements included hemodynamic monitoring, IV fluids, laboratory testing, and ability to provide concomitant medications. The mortality rate was 37% (13 of 35) in patients who received the current standard of care alone and 22% (8 of 36) in patients who received ZMapp in addition to the current standard of care; however, the trial failed to meet the prespecified statistical threshold for efficacy. Based on the results of this prior study, ZMapp was selected by the DRC as the control arm for the PALM study (Protocol 19-I-0003; NCT03719586).

The PALM trial is a Phase 2/3 randomized, controlled, open-label trial designed to study the comparative safety and efficacy of investigational therapeutics in parallel arms compared to ZMapp in patients with known EBOV disease receiving optimized standard of care (oSOC). The trial was sponsored by NIH under IND-125530 and NIH has provided a letter of authorization allowing the FDA to cross-reference their IND in review of Regeneron IND-125507. The initial protocol included three study arms, but was later amended in December 2018 to include REGN-EB3. The other investigational products consist of a recombinant mAb (mAb114, developed by the National Institute of Allergy and Infectious Diseases [NIAID] and Ridgeback Pharmaceuticals) and an IV antiviral drug (remdesivir, also known as GS-5734, developed by Gilead Sciences, Inc.).

3

8. Information related to endpoints used in the available clinical data:

a. Describe the endpoints considered by the sponsor as supporting the BTDR and any other endpoints the sponsor plans to use in later trials. Specify if the endpoints are primary or secondary, and if they are surrogates.

The primary endpoint for comparison in the PALM trial was mortality by Day 28, and consensus for this endpoint was reached with the DRC, WHO, and FDA. Randomization was stratified by baseline RT->22.0)3, Ebola Treatment Unit (ETU) site, and outbreak. Secondary endpoints included virologic and other clinical outcomes (e.g., time to successful discharge from the ETU, mortality up to 58 days after randomization).

b. Describe the endpoint(s) that are accepted by the Division as clinically significant (outcome measures) forpatients with the disease. Consider the following in your response:

Given the challenges of conducting a trial in EVD (e.g., due to the unpredictability of the size and location of outbreaks), REGN-EB3 was initially developed pursuant to the requirements of the Animal Rule. The cocktail was studied in four EBOV challenge studies in nonhuman primates (NHPs) sponsored by BARDA.

As of 9 August 2019, the PALM trial had enrolled 681 subjects of the planned 725 subjects enrolled, but based on the independent review of interim safety and efficacy data from 499 subjects, the DSMB recommended that the PALM study be stopped early because REGN-EB3 was superior to ZMapp in preventing death based on the pre-specified stopping criterion. While the remaining subjects who have been enrolled finish their final assessments (some who were randomized to ZMapp or remdesivir after the trial was halted may have had the option to receive either REGN-EB3 or mAb114), there was an adequate number of subjects assessed to demonstrate a statistically significant comparison between treatment arms. The Sponors (NIH and Regeneron) have not yet reviewed the primary unblinded data, but based on the final assessment of the DSMB, the Division agrees that the statutory requirements needed to pursue approval under the Animal Rule no longer apply.

c. Describe any other biomarkers that the Division would consider likely to predict a clinical benefit for theproposed indication even if not yet a basis for accelerated approval.

The Division has not considered any other biomarkers or surrogate endpoints given that clinical benefit has now been studied in a trial of reasonable size and duration using the primary clinical endpoint of mortality as shown by the results of the PALM trial.

9. A brief description of available therapies, if any, including a table of the available Rx names, endpoint(s) used to establish efficacy, the magnitude of the treatment effects (including hazard ratio, if applicable), and the specific intended population. Consider the following in your response:

There are no approved safe and effective treatments for Ebola virus infection. Standard of care is supportive and may include intravenous fluids, electrolyte monitoring and repletion, oxygen, vasopressors, antiemetics, antidiarrheals, analgesics and treatment of concomitant infections.

10. A brief description of any drugs being studied for the same indication, or very similar indication, that requested breakthrough therapy designation4.

3 Baseline plasma samples with a CT value calculated using nucleoprotein targets. Lower CT values ) are inversely proportionalto viral load and have been shown to predict a significantly higher risk of mortality.4 Biweekly reports of all BTDRs, including the sponsor, drug, and indication, are generated and sent to all CPMSs.4

No other sponsors have requested BTD status for drugs used for the treatment of EVD. Subjects in the PALM trial treated with mAb114 were found to have a similar reduction in mortality as REGN-EB3; therefore, Ridgeback Pharmaceuticals, the current sponsor for mAb114, will likely request BTD as well.

11. Information related to the preliminary clinical evidence:

a. Table of clinical trials supporting the BTDR (only include trials which were relevant to the designation determination decision), including study ID, phase, trial design5, trial endpoints, treatment group(s), number of subjects enrolled in support of specific breakthrough indication, hazard ratio (if applicable), and trial results.

At the time of this BTDR, only preliminary results from the PALM trial are available but demonstrate that patients receiving REGN-EB3 had a statistically greater chance of survival than patients receiving ZMapp or remdesivir. The results were also sufficiently compelling that the DSMB recommended immediate termination of the randomized controlled portion of the study. An extension phase of the study was subsequently implemented that does not include ZMapp and remdesivir treatment arms. Compared to the approximately 50% overall CFR in ZMapp and remdesivir arms, REGN-EB3’s overall CFR was 29%. Only 6% in patients with low baseline viral load (higher CT values) in the REGN-EB3 arm died, compared to 24% in the ZMapp arm. Updates submitted were submitted separately to IND-125530. Treatment arms have been unblinded only to the DSMB and shared with the FDA. Final data analysis is expected in late September/early October 2019. The Sponsor presented topline results available to the public.6 Below is the Sponsor’s table amended based upon the results as unblinded to the DSMB on 8 August 2019.

Table 1: Mortality Rate in the PALM Study (based upon the 8 August 2019 DSMB) Case Fatality Rate a

Overall Low viral load b

ZMapp 63/129 (48.8%) 18/76 (23.7%)

REGN-EB3 32/112 (28.6%) 4/65 (6.2%) mAb114 43/127 (33.9%) 8/74 (10.8%) Remdesivir 70/131 (53.4%) 25/77 (32.5%)

a Reviewer’s note: cross-referencing data submitted directly to the FDA (IND-125530), these estimates are based on outcomes reported among 499 subjects, 123 of whom had vital status only available through at least 10 days from randomization as a proxy for day 28 mortality. This is a reasonable estimate because, based on prior completed reports from the other 376 subjects, 96% who died did so within 10 days of randomization. Among the 24 subjects who died in the REGN-EB3 arm with at least 28 days vital status available, only one died between Day 10 and 28 (on Day 11, EVD-related). One died on Day 40, which was not considered EVD-related. b Reviewer’s note: More precisely (again, cross-referencing IND-125530), these are subjects who had NP CT values >22 (as described by Boseley’s article, most were likely subjects who presented within 24 hours of developing symptoms).

The overall mortality rate among subjects treated with REGN-EB3 in the PALM trial are similar to the interim rates reported from the MEURI EAP (30%, as of April 17, 2019, based on 143 patients).

b. Include any additional relevant information. Consider the following in your response:

The evidence from this trial can be used directly to support the evidence of effectiveness and safety for a BLA. Uncontrolled data from the MEURI EAP can be used to supplement and support the cumulative safety database. With the PALM trial (n=112, with more expected to be unblinded upon the final analysis), there have been 170 patients treated under the MEURI EAP (based on the most recent verbal communication from Regeneron on 16 August 2019), and six healthy volunteers combined for a total of at least 288 subjects who have received the proposed dose 150 mg/kg (single

5 Trial design information should include whether the trial is single arm or multi-arm, single dose or multi-dose, randomized or non-randomized, crossover, blinded or unblinded, active comparator or placebo, and single center or multicenter. 6 Boseley S. Ebola now curable after trials of drugs in DRC, say scientists. The Guardian [newspaper on the internet]. 12 Aug 2019 [cited 12 Aug 2019]. Available from: https://www.theguardian.com/world/2019/aug/12/ebola-now-curable-after-trials-of-drugs-in-drc-say-scientists 5

https://www.theguardian.com/world/2019/aug/12/ebola-now-curable-after-trials-of-drugs-in

intravenous infusion) of REGN-EB3. At this time, there are no significant safety concerns. Common signs and symptoms during infusion of REGN-EB3 that have been described are fevers and chills. At least four patients in the EAP permanently discontinued study drug infusion prior to completion. The signs and symptoms typical of infusion reactions expected with mAbs, however, are also generally consistent with those of EVD. Presence of anti-drug antibodies (ADA) has not been assessed in Ebola-infected patients. Evaluation of PK (including assessment of exposures of individual mAbs using validated assays), immunogenicity, and additional virological data (i.e. viral target epitope mapping and resistance testing) can be assessed in the post-market setting.

12. Division’s recommendation and rationale (pre-MPC review): GRANT:

Provide brief summary of rationale for granting:

The substantial improvement of REGN-EB3 over ZMapp is obvious based on preliminary, but substantial, evidence fromclinical data in the PALM trial.

13. Division’s next steps and sponsor’s plan for future development:

a. If recommendation is to grant the request, explain next steps and how the Division would advise the sponsor (for example, plans for phase 3, considerations for manufacturing and companion diagnostics, considerations for accelerated approval, recommending expanded access program):

The Agency has a planned face-to-face meeting on 4 September 2019 to discuss the proposed commercial manufacturing process, which is different from the process used to generate the clinical lots. Regeneron will provide data demonstrating comparability between the different processes. We note that Regeneron already has four marketed products that have successfully demonstrated comparability between the clinical and commercial platform processes for these mAbs. There is an adequate supply to support the extension phase of the ongoing PALM trial, as it appears Regeneron was holding onto supply to support the healthy human volunteer trial, but that may not be needed now that the interim topline results of the PALM trial are now available.

The ultimate plan is to work with Regeneron to submit a traditional BLA as soon as feasible. Originally it was presumed that the BLAs would be submitted under the Animal Rule, but now that clinical data from the PALM trial are available, this approach is no longer necessary. Our intent is to expedite reviews once a BLA is submitted, and this may be facilitated by a rolling review process. Uncontrolled clinical data from the MEURI EAP will be considered to further support the clinical safety of REGN-EB3, and NHP efficacy studies will be considered supportive of the clinical efficacy data.

b. If recommendation is to deny the request and the treatment looks promising, explain how the Division would

advise the sponsor regarding subsequent development, including what would be needed for the Division toreconsider a breakthrough therapy designation: N/A

14. List references, if any:

1. Boseley S. Ebola now curable after trials of drugs in DRC, say scientists. The Guardian [newspaper on the internet]. 12 Aug 2019 [cited 12 Aug 2019]. Available from: https://www.theguardian.com/world/2019/aug/12/ebola-now-curable-after-trials-of-drugs-in-drc-say-scientists

2. News Release from NIH/NIAID. Independent Monitoring Board Recommends Early Termination of Ebola Therapeutics Trial in DRC Because of Favorable Results with Two of Four Candidates. 12 Aug 2019 [accessed 20 Aug 2019]. Available from: https://www niaid nih.gov/news-events/independent-monitoring-board-recommends-early-termination-ebola-therapeutics-trial-drc

3. The PREVAIL II Writing Group, for the Multi-National PREVAIL II Study Team. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med 2016;375(15):1448-56.

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https://wwwhttps://www.theguardian.com/world/2019/aug/12/ebola-now-curable-after-trials-of-drugs-in-drc-say-scientists

15. Is the Division requesting a virtual MPC meeting via email in lieu of a face-to-face meeting?YES NO

16. Clearance and Sign-Off (after MPC review):

Grant Breakthrough Therapy Designation Deny Breakthrough Therapy Designation

Reviewer Signature: {See appended electronic signature page} Team Leader Signature: {See appended electronic signature page} Division Director Signature: {See appended electronic signature page}

Revised 3/18/19/M. Raggio

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

Isl

BENJAMIN D LORENZ 0812712019 01 :54:27 PM

KIMBERLY A STRUBLE 0812712019 02:36:24 PM

DEBRA B BIRNKRANT 0812712019 03:48:44 PM


Structure BookmarksCENTER FOR DRUG EVALUATION AND. RESEARCH. CENTER FOR DRUG EVALUATION AND. RESEARCH. APPLICATION NUMBER:.

761169Orig1s000. 761169Orig1s000. ADMINISTRATIVE and CORRESPONDENCE .DOCUMENTS. ADMINISTRATIVE and CORRESPONDENCE .DOCUMENTS.

FigureIND 125507..MEETING MINUTES Regeneron Pharmaceuticals, Inc. Attention: Janie Parrino, MD Senior Director, Regulatory Affairs 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 Dear Dr. Parrino: Please refer to your investigational new drug application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for REGN3470-3471-3479 (REGNEB3). -

We also refer to the telecon between representatives of your firm and the FDA on October 21, 2019. The purpose of the meeting was to discuss the content and format of a BLA. A copy of the official minutes of the telecon is enclosed for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes. If you have any questions, call me, at (301) 796-0824. Sincerely, {See appended electronic signature page} Elizabeth Thompson, MS Senior Program Management Officer Division of Antiviral Products Office of Antimicrobial Products Center for Drug Evaluation and Research Enclosure: Meeting Minutes Figure

FigureMEMORANDUM OF MEETING MINUTES..Meeting Type: Meeting Category: Meeting Type: Meeting Category: Meeting Type: Meeting Category: B Pre-BLA

Meeting Date and Time: Meeting Location: Meeting Date and Time: Meeting Location: October 21, 2019; 10:00 AM – 11:30 AM EST Teleconference

Application Number: Product Name: Application Number: Product Name: IND 125507 REGN3470-3471-3479 (REGN-EB3)

Indication: Sponsor Name: Indication: Sponsor Name: Treatment of Ebola virus infection Regeneron Pharmaceuticals, Inc.

FDA ATTENDEES FDA ATTENDEES

Office of New Drugs Office of New Drugs

Katherine Schumann, MS, OND Policy Staff Barbara Styrt, MD, Medical Officer Office of Antimicrobial Products

Debbie Birnkrant, MD, Director Jeff Murray, MD, MPH, Deputy Director Karen Winestock, Chief, Project Management Staff Elizabeth Thompson, MS, Senior Program Management Officer Ben Lorenz, MD, Clinical Reviewer Kim Struble, PharmD, Clinical Team Leader John Dubinion, PhD, Nonclinical Reviewer Chris Ellis, PhD, Nonclinical Team Leader Eric Donaldson, PhD, Clinical Virology Reviewer Jules O’Rear, PhD, Clinical Virology Team Leader Mario Sampson, PhD, Clinical Pharmacology Reviewer Su-Young Choi, PhD, Clinical Division of Antiviral Products

Karen Bleich, MD, Medical Officer Office of Scientific Investigations

Marquita Burnett, MPH, Regulatory Business Project Manager Marquita Burnett, MPH, Regulatory Business Project Manager Office of Biotechnology Products (OBP)/Office of Product Quality (OPQ)

IND 125507 Page 2

Tzanko Stantchev, PhD, Drug Product Reviewer Marjorie Shapiro, PhD, Lab Chief Gerald Poley, MD, Medical Officer Susan McDermott, MD, Medical Officer Kara Bertolaccini, PharmD, Regulatory Project Manager Counter-Terrorism and Emergency Coordination Staff

SPONSOR ATTENDEES Regeneron Regeneron

Ned Braunstein, MD, Sr VP, Regulatory Affairs Janie Parrino, MD, Sr Director, Regulatory Affairs Elizabeth Bradley, MS, PharmD, Manager, Regulatory Affairs Leah Lipsich, PhD, VP, Strategic Program Direction Yasmin Khan, MS, MPH, Director, Development Program Management Eduardo Forleo Neto, MD, MSc, Exec Director, Clinical Sciences Sumathi Sivapalasingam, MD, Sr Director, Clinical Sciences Bret Musser, PhD, Sr Director, Biostatistics Meilin Huang, PhD, Principal Biostatistician Christos Kyratsous, PhD, VP, RDavid Boucher, PhD, Chief, Antivirals & Antitoxins, CBRN Danielle Turley, PhD, Project Officer, AVAT, CBRN Michael Merchlinsky, PhD, Scientific Program Manager, CBRN Paul Roney, PhD, DABT, Regulatory Specialist, RQA James Wangelin, MS, MBA, RAC, Regulatory Specialist, RQA BARDA

1.0 BACKGROUND 1.0 BACKGROUND Regeneron Pharmaceuticals, Inc. (Regeneron) requested a Type B pre-BLA meeting on September 20, 2019 to discuss the content and format of a BLA application for REGN3470-3471-3479, also known as REGN-EB3. Having recently received Breakthrough Therapy Designation, this meeting also serves as the Breakthrough Therapy-Initial Comprehensive meeting. The background package was submitted with U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov www.fda.gov

IND 125507 Page 3 the meeting request, and an addendum that included non-human primate (NHP) data and a supplemental statistical analysis plan (SAP) to the NIH PALM RCT SAP was provided on October 9, 2019. REGN-EB3, is a cocktail of three human IgG1 monoclonal antibodies (mAbs) directed against different, non-overlapping epitopes on Ebola virus (EBOV) glycoprotein (GP). Regeneron initiated the REGN-EB3 development program under the Animal Rule, but with the advent of the Ebola outbreak in the North Kivu province of the Democratic Republic of the Congo (DRC) in 2018, Regeneron has accrued data in Ebola-infected patients and will follow a traditional pathway to approval. Regeneron proposes the randomized controlled trial (RCT; PALM study, protocol 19-I-0003) conducted by the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH, I-

REGN-EB3 was granted orphan-drug designation for the treatment of Ebola virus infection on July 14, 2016 and granted Breakthrough Therapy Designation on September 3, 2019. FDA granted the meeting on September 27, 2019 and sent Preliminary Comments to Regeneron on October 15, 2019.

2.0 DISCUSSION 2.0 DISCUSSION 2.1. Clinical 2.1. Clinical Does the Agency agree that a single IV infusion of 150 mg/kg of REGN-EB3 is the to-be-marketed dose provided the final results from the PALM study are consistent with the data shared to date? Question 1:

We agree. Although the 150 mg single dose is acceptable for an initial marketing approval, we do not have enough data to determine whether this is the optimal dose. We recommend that you propose a plan to conduct additional nonclinical and/or clinical studies post-approval to further optimize the dosing regimen. FDA Response to Question 1:

We have recommended assessment of higher doses, particularly for subjects who present with CT values

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